Osteosarcoma risk in rats using PTH 1-34.

article is a good review of the efficacy of the first parathyroid hormone to treat osteoporosis, PTH 1-34, including the limits of that efficacy. We would like to bring attention to the fact that there is a primary safety issue (the induction of osteosarcomas in a rat carcinogenicity study) related to the use of PTH 1-34, which was discussed at some length in the article by Neer et al. 2 In trials with rats, osteosarcomas occurred in rats treated from the age of six to seven weeks for two years with PTH 1-34 (representing near lifetime treatment) at frequencies of 0%, 5%, 35% and 52% (control, low, middle and high dose) in males and in 0%, 7%, 20% and 38% of females 'no-effect level'for osteosarcomas was established because tumors were present at even the lowest dose tested. There was also a statistically significant increase in osteoblastomas in both sexes. As a result of these findings, the clinical trials were prematurely stopped in December 1998. Consequently, the median treatment duration was only 19 months for the main trial, rather than the three years that were originally planned The human significance of these osteosarcomas has been rationalized away by citing: (1) the lack of osteosarcomas in the clinical trial; (2) the absence of bone tumors in an 18-month monkey study; (3) the lack of genotoxicity; and (4) the lack of tumors in patients with hyperparathyroidism. The absence of bone tumors in the clinical trial patients is not surprising given that osteosarcomas are rare and the time to appearance for chemically induced tumors, in general, ranges from ten to 20 years from the time of exposure. Similarly, the monkey study was much too short (not lifetime) and lacked statistical power, having only four monkeys per group rather than the 60 individuals per group in the rat study. Because the formation of osteosarcomas is mechanism based (PTH stimulates proliferation of osteoblasts, thus increasing the likelihood of mutations), the absence of positive results in genotoxicity tests is not relevant. A probable mechanism for carcinogenicity is drug-induced cell division, increasing the chances for generating genetic errors and then magnifying them. Finally, that osteosarcomas are not seen in patients with hyperparathyroidism is of limited relevance, because those patients are exposed to chronically elevated PTH levels, whereas patients being treated with PTH are on an intermittent dosing schedule, which can induce a differential effect on osteoblastic gene expression …